Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]­pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]­pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 g/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054,522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.Somatostatin is widely distributed throughout the central nervous system and various endocrine tissues (1-3). Two biologically active forms of somatostatin are known, a 14-amino acid peptide and an N-terminal extended peptide with 28 amino acids (4 -6). Somatostatin has multiple functions, including modulation of growth hormone, insulin, glucagon, and gastric acid secretion (3, 7-10). Five somatostatin receptors (sst1-5) have been cloned and characterized (11)(12)(13)(14). All five receptors are members of the G protein-linked receptor family (15). Structure-function studies with a large number of peptidal analogs have shown that the Trp 8 -Lys 9 dipeptide of somatostatin is necessary for high-affinity binding (16) and have facilitated the development of potent analogs, including SMS 201-955 (Sandostatin or octreotide) which is clinically used for the treatment of acromegaly and certain endocrine tumors (17-19). We describe here strategies that were successful in designing small molecule subtype 2-selective agonists whose potencies on this receptor exceed somatostatin. Studies utilizing one of these subtype-selective somatostatin peptidomimetics, L-054,522, in both in vivo and in vitro experiments demonstate that somatostatin receptor subtype 2 (sst2) mediates the inhibition of growth hormone release from the rat anterior pituitary as well as glucagon from the rat pancreas. Insulin release is only inhibited at significantly higher concentrations of the compound. These results suggest possible therapeutic applications of selective sst2 agonists. Compound 4 was initially synthesized in a combinatorial library consisting of 20 diamines, 20 amino acids, and 79 amines. The diamines were linked to 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid functionalized Tentagel resin via urethane chemistry in a regiorandom way. 9-Fluorenylmethoxycarbonyl amino acids were coupled to the amine resins using standard 1,3-diisopropylcarbodiimide coupling. The 9-fluorenylmethoxycarbonyl groups were removed with piperidine and activated with p-nitrophenyl chloroformate before ...

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A structure-activity relationship study of the imidazolyl-β-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.